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Background: Valve‐in‐valve (ViV) transcatheter aortic valve replacement (TAVR) offers an alternative to reoperative surgical aortic valve replacement. The short‐ and intermediate‐term outcomes after ViV TAVR in the real world are not entirely clear. Patients and Methods: A multicenter, retrospective analysis of a consecutive series of 121 ViV TAVR patients and 2200 patients undergoing primary native valve TAVR from 2012 to 2017 at six medical centers. The main outcome measures were in‐hospital mortality, 30‐day mortality, stroke, myocardial infarction, acute kidney injury, and pacemaker implantation. Results: ViV patients were more likely male, younger, prior coronary artery bypass graft, "hostile chest," and urgent. 30% of the patients had Society of Thoracic Surgeons risk score <4%, 36.3% were 4%–8% and 33.8% were >8%. In both groups many patients had concomitant coronary artery disease. Median time to prosthetic failure was 9.6 years (interquartile range: 5.5–13.5 years). 82% of failed surgical valves were size 21, 23, or 25 mm. Access was 91% femoral. After ViV, 87% had none or trivial aortic regurgitation. Mean gradients were <20 mmHg in 54.6%, 20–29 mmHg in 30.6%, 30–39 mmHg in 8.3% and ≥40 mmHg in 5.87%. Median length of stay was 4 days. In‐hospital mortality was 0%. 30‐day mortality was 0% in ViV and 3.7% in native TAVR. There was no difference in in‐hospital mortality, postprocedure myocardial infarction, stroke, or acute kidney injury. Conclusion: Compared to native TAVR, ViV TAVR has similar peri‐procedural morbidity with relatively high postprocedure mean gradients. A multidisciplinary approach will help ensure patients receive the ideal therapy in the setting of structural bioprosthetic valve degeneration. [ABSTRACT FROM AUTHOR]

Abstract: A statewide qualitative study of personal and organizational factors contributing to employees'' decisions to either remain or leave employment in child welfare is described. Of particular interest was identifying factors related to employee retention. Professional staff (n =369) in a state public child welfare agency, representing all levels of the agency and regions of the state, participated in 58 focus group interviews comprising some 1200 person hours of data collection. Core findings of the results are presented and discussed in view of information from other recent child welfare workforce studies. Recommendations and implications of the results for policy and practice are described. [Copyright &y& Elsevier]

The hetero-oligomeric complex of the FlhD and FlhC proteins (FlhDC) regulates transcription from several flagellar and non-flagellar operons in bacteria. The crystallographic structure of the Escherichia coli FlhDC complex has been solved to 3.0Å resolution, revealing a hexameric FlhD4FlhC2 assembly. In the complex, each FlhC protomer binds an FlhD2 dimer; the conformation of the dimer in the complex differs significantly from its conformation in the absence of FlhC. FlhC has a novel tertiary fold that includes a heretofore unrecognized zinc-binding site in which the ion is ligated by four cysteine residues. Gel shift experiments show that binding of the FlhDC complex to a cognate promoter bends the DNA by approximately 111°. The structure of the FlhDC complex is compatible with models in which a fragment of operator DNA, at least 48 base-pairs in length, wraps around the complex and bends significantly when binding. [Copyright &y& Elsevier]

Clinicians frequently assess and intervene on postural alignment; however, notions of what constitutes good postural alignment are variable. Furthermore, the majority of current evidence appeals either to population norms or defines good postural alignment as the negation of what has been observed to correlate with pathology. The purpose of this study was to identify affirmative indicators of good postural alignment in reference to motor control theory. Electromyography (anterior leg, posterior leg, and trunk muscles) and motion capture data were acquired from 13 participants during 4 min bipedal standing trials in 4 conditions: control, − 10%, + 30%, and + 60% of subject-specific anterior limits of stability. Synergistic kinematic coordination was quantified via the uncontrolled manifold framework, and correlated neural drive was quantified in posture-relevant muscle groups (anterior, posterior, and trunk) via intermuscular coherence. Multilevel models assessed the effects of sagittal plane alignment on both outcomes. We observed a within-subjects fixed effect in which kinematic synergistic coordination decreased as subjects became more misaligned. We also observed within-subjects fixed effects for middle- and high-frequency intermuscular coherence in the posterior group (increased coherence with increased misalignment) and for trunk intermuscular coherence across all frequency bands (decreased coherence with increased misalignment). Our findings indicate that it may be possible to describe healthy postural alignment in light of referent control theory. Greater misalignment with respect to vertical is associated with compromises in synergistic control of posture and increased corticospinal drive to specific muscle groups. These results suggest that postural alignment may not simply be an empirical phenomenon. [ABSTRACT FROM AUTHOR]

Aims: Emerging data support that submucosa-invasive (pT1b) esophageal adenocarcinomas are cured via endoscopic resection, provided that invasion measures =500 lm, they lack other histological features predictive of nodal metastasis and have negative margins. Hence, pathologists' measurement of the depth of submucosal invasion in endoscopic resections may dictate further management (i.e. endoscopic follow-up versus oesophagectomy). In this study, we assessed the interobserver agreement in measuring the depth of submucosal invasion in oesophageal endoscopic resections. Methods and results: Six subspecialised gastrointestinal (GI) pathologists from five academic centres independently measured the depth of submucosal invasion in lm from the deepest muscularis mucosae on 37 oesophageal endoscopic resection slides (round 1 scoring). A consensus meeting with a systematic approach for measuring and discussion of pitfalls was undertaken and remeasuring (round 2 scoring) was conducted. Interobserver agreement was assessed by the intraclass correlation coefficient (ICC) and Cohen's kappa statistics. A lack of agreement was seen among the six reviewers with a poor ICC for both rounds: 1 [0.40, 95% confidence interval (CI) = 0.26-0.56] and 2 (0.49, 95% CI = 0.34-0.63). When measurements were categorised as < or >500 lm, the overall agreement among the six reviewers was only fair for both rounds: 1 (kappa = 0.37, 95% CI = 0.22-0.53) and 2 (kappa = 0.29, 95% CI = 0.12-0.46). Conclusions: Our study shows a lack of agreement among gastrointestinal pathologists in measuring the depth of submucosal invasion in oesophageal endoscopic resections despite formulating a consensus approach for scoring. If important management decisions continue to be based upon this parameter, more reproducible and concrete guidelines are needed. [ABSTRACT FROM AUTHOR]

3D processed silicon detectors offer several advantages over conventional, planar processed devices. The electric fields between the electrodes of a 3D detector are parallel to its surface, and for a given applied bias, stronger than those found in a planar device of equivalent dimensions. We have investigated the spatial response of a first generation 3D detector using a synchrotron X-ray microbeam as a probe. The microbeam was of cross-section ∼10 μm, commensurate with the dimensions of the electrode structures. The detector showed excellent charge collection, as verified by the energy spectra acquired at various probe positions. Variations in the energy spectra provided a sensitive indicator of the charge splitting that inevitably occurs at the boundaries between adjacent pixel cells, and for measuring the expected loss of sensitivity at the 3D electrodes themselves. [Copyright &y& Elsevier]

Background: Readmissions after cardiac surgery are common and associated with increased morbidity, mortality and cost of care. Policymakers have targeted coronary artery bypass grafting to achieve value-oriented health care milestones. We explored the causes of readmission following cardiac surgery among a regional consortium of hospitals.Methods: Using administrative data, we identified patients readmitted to the same institution within 30 days of cardiac surgery. We performed standardized review of readmitted patients' medical records to identify primary and secondary causes of readmission. We evaluated causes of readmission by procedure and tested for univariate associations between characteristics of readmitted patients and nonreadmitted patients in our clinical registry.Results: Of 2218 cardiac surgery patients, 272 were readmitted to the index hospital within 30 days for a readmission rate of 12.3%. Median time to readmission was 9 days (interquartile range 4-16 days) and only 13% of patients were evaluated in-office before readmission. Readmitted patients were more likely to have had valve surgery (31.3% vs 22.7%) than patients not readmitted. Readmitted patients were also more likely to have preoperative creatinine more than or equal to 2 mg/dL (P = .015) or congestive heart failure (CHF) (P = .034), require multiple blood transfusions or sustained inotropic support (P < .001), and experience postoperative atrial fibrillation (P = .022) or renal insufficiency (P < .001). Infection (26%), pleural or pericardial effusion (19%), arrhythmia (16%), and CHF (11%) were the most common primary etiologies leading to readmission.Conclusions: Ensuring early follow-up for high-risk patient groups while improving early detection and management of the principal drivers of readmission represent promising targets for decreasing readmission rates. [ABSTRACT FROM AUTHOR]

Background: Although previous studies have demonstrated that patients receiving bilateral internal mammary artery (BIMA) conduits during coronary artery bypass grafting have better long-term survival than those receiving a single internal mammary artery (SIMA), data on risk of repeat revascularization are more limited. In this analysis, we compare the timing, frequency, and type of repeat coronary revascularization among patients receiving BIMA and SIMA.Methods: We conducted a multicenter, retrospective analysis of 47 984 consecutive coronary artery bypass grafting surgeries performed from 1992 to 2014 among 7 medical centers reporting to a prospectively maintained clinical registry. Among the study population, 1482 coronary artery bypass grafting surgeries with BIMA were identified, and 1297 patients receiving BIMA were propensity-matched to 1297 patients receiving SIMA. The primary end point was freedom from repeat coronary revascularization.Results: The median duration of follow-up was 13.2 (IQR, 7.4-17.7) years. Patients were well matched by age, body mass index, major comorbidities, and cardiac function. There was a higher freedom from repeat revascularization among patients receiving BIMA than among patients receiving SIMA (hazard ratio [HR], 0.78 [95% CI, 0.65-0.94]; P=0.009). Among the matched cohort, 19.4% (n=252) of patients receiving SIMA underwent repeat revascularization, whereas this frequency was 15.1% (n=196) among patients receiving BIMA (P=0.004). The majority of repeat revascularization procedures were percutaneous coronary interventions (94.2%), and this did not differ between groups (P=0.274). Groups also did not differ in the ratio of native versus graft vessel percutaneous coronary intervention (P=0.899), or regarding percutaneous coronary intervention target vessels; the most common targets in both groups were the right coronary (P=0.133) and circumflex arteries (P=0.093). In comparison with SIMA, BIMA grafting was associated with a reduction in all-cause mortality at 12 years of follow-up (HR, 0.79 [95% CI, 0.69-0.91]; P=0.001), and there was no difference in in-hospital morbidity.Conclusions: BIMA grafting was associated with a reduced risk of repeat revascularization and an improvement in long-term survival and should be considered more frequently during coronary artery bypass grafting. [ABSTRACT FROM AUTHOR]

L7648 --> 824.1 --> Cardiovascular diseases (CVD) are a significant cause of morbidity and mortality, especially in the elderly population and they represent an important risk factor for frailty. The essential amino acid, tryptophan (TRP), acts as a precursor of neurotransmitters/hormones, such as serotonin and melatonin, and is central to many aspects of cellular metabolism. TRP degradation, however, can lead to breakdown products, such as kynurenine (KYN), whose impact on normal and diseased hearts remains primarily unknown. Moreover, in recent clinical reports, increased levels of KYN and/or its metabolites, formed via degradation of the essential amino acid tryptophan, are associated with heart diseases and atherosclerosis. KYN infusion significantly impaired cardiac function in Langendorff‐perfused hearts. Similarly in isolated cardiomyocytes, exposure to KYN increased oxidative stress and decreased fractional shortening. The ongoing studies include mechanistic approaches to determine the pathways involved in KYN and/or its metabolites' impact on myocardial function. [ABSTRACT FROM AUTHOR]

Ataxia-telangiectasia is a genetic disorder associated with high incidence of B-cell lymphoma. Using an ataxiatelangiectasia mouse model, we compared lymphoma incidence in several isogenic mouse colonies harboring different bacterial communities, finding that intestinal microbiota are a major contributor to disease penetrance and latency, lifespan, molecular oxidative stress, and systemic leukocyte genotoxicity. High-throughput sequence analysis of rRNA genes identified mucosa-associated bacterial phylotypes that were colony-specific. Lactobacillus johnsonii, which was deficient in the more cancer-prone mouse colony, was causally tested for its capacity to confer reduced genotoxicity when restored by short-term oral transfer. This intervention decreased systemic genotoxicity, a response associated with reduced basal leukocytes and the cytokine-mediated inflammatory state, and mechanistically linked to the host cell biology of systemic genotoxicity. Our results suggest that intestinal microbiota are a potentially modifiable trait for translational intervention in individuals at risk for B-cell lymphoma, or for other diseases that are driven by genotoxicity or the molecular response to oxidative stress. [ABSTRACT FROM AUTHOR]

Approximately 1 in 5 patients undergoing cardiac surgery are readmitted within 30 days of discharge. Among the primary causes of readmission are infection and disease states susceptible to the inflammatory cascade, such as diabetes, chronic obstructive pulmonary disease, and gastrointestinal complications. Currently, it is not known if a patient's baseline inflammatory state measured by crude white blood cell (WBC) counts could predict 30-day readmission. We collected data from 2,176 consecutive patients who underwent cardiac surgery at seven hospitals. Patient readmission data was abstracted from each hospital. The independent association with preoperative WBC count was determined using logistic regression. There were 259 patients readmitted within 30 days, with a median time of readmission of 9 days (IQR 4-16). Patients with elevated WBC count at baseline (10,000-12,000 and >12,000mm3) had higher 30-day readmission than those with lower levels ofWBC count prior to surgery (15% and 18% compared to 10%-12%, P = 0.037). Adjusted odds ratios were 1.42 (0.86, 2.34) for WBC counts 10,000-12,000 and 1.81 (1.03, 3.17) for WBC count > 12,000. We conclude that WBC count measured prior to cardiac surgery as a measure of the patient's inflammatory state could aid clinicians and continuity of care management teams in identifying patients at heightened risk of 30-day readmission after discharge from cardiac surgery. [ABSTRACT FROM AUTHOR]

CheY is a member of the response regulator protein superfamily that controls the chemotactic swimming response of motile bacteria. The CheY double mutant D13K Y106W (CheY**) is resistant to phosphorylation, yet is a highly effective mimic of phosphorylated CheY in vivo and in vitro. The conformational attributes of this protein that enable it to signal in a phosphorylation-independent manner are unknown. We have solved the crystal structure of selenomethionine-substituted CheY** in the presence of its target, a peptide (FliM16) derived from the flagellar motor switch, FliM, to 1.5Å resolution with an R-factor of 19.6%. The asymmetric unit contains four CheY** molecules, two with FliM16 bound, and two without. The two CheY** molecules in the asymmetric unit that are bound to FliM16 adopt a conformation similar to -activated wild-type CheY, and also bind FliM16 in a nearly identical manner. The CheY** molecules that do not bind FliM16 are found in a conformation similar to unphosphorylated wild-type CheY, suggesting that the active phenotype of this mutant is enabled by a facile interconversion between the active and inactive conformations. Finally, we propose a ligand-binding model for CheY and CheY**, in which Ile95 changes conformation in a Tyr/Trp106-dependent manner to accommodate FliM. [Copyright &y& Elsevier]

FlhD is a 13.3 kDa transcriptional activator protein of flagellar genes and a global regulator. FlhD activates the transcription of class II operons in the flagellar regulon when complexed with a second protein FlhC (21.5 kDa). FlhD also regulates other expression systems in Escherichia coli . We are seeking to understand this plasticity of FlhD's DNA-binding specificity and, to this end, we have determined the crystal structure of the isolated FlhD protein. The structure was solved by substituting seleno-methionine for natural sulphur-methionine in FlhD, crystallizing the protein and determining the structure factor phases by the method of multiple-energy anomalous dispersion (MAD). The FlhD protein is dimeric. The dimer is tightly coupled, with an intimate contact surface, implying that the dimer does not easily dissociate. The FlhD monomer is predominantly α-helical. The C-termini of both FlhD monomers (residues 83–116) are completely disrupted by crystal packing, implying that this region of FlhD is highly flexible. However, part of the C-terminus structure in chain A (residues 83–98) was modelled using a native FlhD crystal. What is seen in chain A suggests a classic DNA-binding, helix–turn–helix (HTH) motif. FlhD does not bind DNA by itself, so it may be that the DNA-binding HTH motif becomes rigidly defined only when FlhD forms a complex with some other protein, such as FlhC. If this were true, it might explain how FlhD exhibits plasticity in its DNA-binding specificity, as each partner protein with which it forms a complex could allosterically affect the binding specificity of its HTH motif. A disulphide bridge is seen between the unique cysteine residues (Cys-65) of FlhD native homodimers. Alanine substitution at Cys-65 does not affect FlhD transcription activator activity, suggesting that the disulphide bond is not necessary for either dimer stability or this function of FlhD. Electrostatic potential analysis indicates... [ABSTRACT FROM AUTHOR]

Twenty hatchling chickens were injected intravitreally every 4 days from day 2 to day 16 with dimethyl sulphoxide (DS) in one eye and DS or formoguanamine dissolved in DS (FG.DS) with or without occlusion in the other (FG.DS.MD, DS.MD, FG.DS). At day 16, the FG.DS.MD eyes failed to show the high refractive myopia and showed less axial elongation than that developed by the DS.MD eyes. Electroretinograms indicated that at the dosage used, FG.DS does not eliminate phototransduction. Light microscopy showed choroidal and retinal thinning in DS.MD and FG.DS.MD eyes but less than in FG.DS eyes, suggesting that change in choroidal thickness is unlikely to be the primary cause of form deprivation myopia.